Deciphering mechanisms of Listeria placental-fetal invasion

项目摘要 单核细胞增生李斯特菌（Lm）是一种兼性革兰氏阳性细胞内细菌， 通过摄入受污染的食物感染人类。严重感染可发生在老年人和 免疫功能低下的患者以及孕妇和新生儿。感染可导致 脑膜炎、脑膜脑炎、脑脓肿，孕妇流产、死产， 播散性胎儿感染尽管使用抗生素，侵袭性Lm病的死亡率仍很高 治疗突出了对新的有效治疗策略的需要，用于管理Lm感染。 先前的研究表明，不同的Lm分离株可以表现出不同的组织向性， 获得新的靶器官复制利基。发现一株临床分离的Lm，07 PF 0776， 具有增强的靶向心脏组织的能力， InlB是一种与宿主细胞侵袭相关的细菌表面蛋白。这些氨基酸变异 似乎增加了稳定性并促进了与宿主表面硫酸肝素部分的结合， 导致InlB募集到宿主细胞表面，并刺激Met， InlB. Met受体由胎盘组织大量表达，并且是胚胎发育所需的， 胎盘发育初步数据显示，至少有两种Lm亲心菌株表达 InlB变体表现出显著增强垂直透射。我们假设， InlB的表达可以扩大Lm的组织库，并通过Met的操纵增强侵袭力。 信号通路，导致胎儿传播率增加。本提案的具体目标 将对Lm InlB变异株进行功能评估，以检查它们在垂直免疫中的功效。 以及确定过表达和/或增加稳定性的机制 InlB增加垂直传输。目标1将进行心功能评估 菌株的垂直传播效率，以定义和鉴定Lm菌株， 增加胎儿疾病的风险。目的2将确定过度表达的机制， InlB增加Lm垂直传输。因此，这些研究将阐明选择性Lm分离株如何获得 高效接触胎盘/胎儿组织，导致毁灭性的新生儿疾病 与死

Project Summary Listeria monocytogenes (Lm) is a facultative gram-positive intracellular bacterium that causes infection in humans via ingestion of contaminated food. Severe infection can occur in elderly and immunocompromised patients well as in pregnant women and neonates. Infection can lead to meningitis, meningoencephalitis, brain abscess, and, for pregnant women, abortion, still-birth, and disseminated fetal infection. The high mortality rate of invasive Lm disease despite antibiotic treatment highlights the need for new effective therapeutic strategies for managing Lm infections. Previous studies have shown that distinct isolates of Lm can exhibit different tissue tropisms, resulting in the acquisition of novel target organ replication niches. A clinical Lm isolate, 07PF0776, was found to have an enhanced ability to target cardiac tissue based on amino acid variations present within InlB, a bacterial surface protein associated with host cell invasion. These amino acid variations appear to increase stability and promote binding to host surface heparin sulfate moieties, which results in recruitment of InlB to the host cell surface and stimulation of Met, the receptor bound by InlB. The Met receptor is abundantly expressed by placental tissue and is required for embryonic and placental development. Preliminary data has shown at least two Lm cardiotropic strains expressing the InlB variant exhibit significantly enhanced vertical transmission. We hypothesize that modification of InlB can expand the tissue repertoire of Lm and enhance invasion through the manipulation of Met signaling pathways, leading to increased rates of fetal transmission. The specific aims of this proposal will undertake a functional assessment of Lm InlB variant strains to examine their efficacy of vertical transmission as well as determine the mechanisms by which overexpression and/or increased stability of InlB increases vertical transmission. Aim 1 will undertake a functional assessment of cardiotropic strains for efficiency of vertical transmission to define and identify strains of Lm that pose an enhanced risk for fetal disease. Aim 2 will determine the mechanisms by which overexpression of InlB increases Lm vertical transmission. These studies will thus clarify how select Lm isolates gain access with high efficiency to placental/fetal tissues to cause devastating forms of neonatal disease and death.